Harnessing microbial iron chelators to develop innovative therapeutic agents

BACKGROUND: Bacterial infections involving multidrug-resistant Gram-negative bacteria have become critically involved in the current antibiotic crisis. This, together with the bacterial evolution ability, prioritizes the discovery of new antibiotics. Research on microbial iron acquisition pathways and metabolites, particularly siderophores, has highlighted hopeful aspects for the design of advanced antimicrobial approaches. Moreover, exploiting siderophores machinery to treat diseases associated with iron overload and cancer is of additional interest for the therapeutic arena. AIM OF REVIEW: This review highlights and provides a renewed perspective on the evolutionary path of siderophores, from primordial siderophores to new iron chelating agents, stimulating the field to build on the past and shape the future. KEY SCIENTIFIC CONCEPTS OF REVIEW: The effectiveness of siderophore-mimicking antibiotics appears to be high and selective for Gram-negative pathogens, rendering multidrug-resistant (MDR) bacteria susceptible to killing. Herein, cefiderocol, a new siderophore antibiotic, is well positioned in the clinic to treat MDR infections instigated by Gram-negative bacteria, particularly urinary tract infections and pneumonia. This siderophore has a mode of action based on a “Trojan horse” strategy, using the iron uptake systems for efficient bacterial penetration and killing. Recent progress has also been achieved concerning new iron chelating compounds to treat diseases associated with iron overload and cancer. Though these compounds still face great challenges for a clinical application, their promising results open up new doors for the design and development of innovative iron chelating compounds, taking benefit from the structurally diverse nature of siderophores.